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Background: Osteosarcoma is the most prevalent primary malignant bone tumor containing mesenchymal cells with poor prognosis. Being a hot spot of anti-tumor therapy researches, AKT/mammalian target of rapamycin (mTOR) signaling pathway could affect various cellular processes including transcription, protein synthesis, apoptosis, autophagy and growth. Materials and methods: The levels of RNA and protein were detected by quantitative real-time polymerase chain reaction (q-PCR) and western blot analyses respectively. Functional assays were carried out to analyze the malignant phenotypes of osteosarcoma cells. RNA-binding protein immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP), RNA pulldown, luciferase reporter and in vitro kinase assays were conducted to uncover the specific mechanism of microRNA-451a (miR-451a) in osteosarcoma cells. Results: Functionally, miR-451a represses the malignant progression of osteosarcoma. Mechanically, miR-451a could curb the AKT/mTOR pathway via 3-phosphoinositide dependent protein kinase 1 (PDPK1)-mediated phosphorylation modification. After the certification that YTH domain containing 1 (YTHDC1) regulates the m6A phosphorylation modification of PDPK1 mRNA, we further proved that miR-451a-mediated YTHDC1 stabilizes PDPK1 mRNA via m6A-dependent regulation. Conclusion: This study demonstrated that miR-451a regulates YTHDC1-mediated m6A methylation to activate the AKT/mTOR pathway, stimulating the malignancy of osteosarcoma.